Derivatives of dibenzo cycloocten-5,11-imine

ABSTRACT

Compounds of the class of 5,6,11,12-tetrahydrodibenzo(a, e)cycloocten-5,11-imine and the pharmaceutically acceptable acid addition salts thereof have anti-tussive and simultaneously musculotropic spasmolytic activities; they are the active ingredients of pharmaceutical compositions and can be used for the treatment of tussive irritation; an illustrative embodiment is 2-methoxy-5,6,11,12-tetrahydrodibenzo(a,e)cycloocten-5,11imine hydrochloride.

United States Patent 1 Kocsis et al.

[54] DERIVATIVES OF DIBENZO CYCLOOCTEN-SJl-HWINE [75] Inventors: KarolyKocsis, Basel; Ulrich Renner, Riehen; Knnt Alfred Jaeggi, Basel,

all of Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: May27, 1970 211 App]. No.: 41,099

[30] Foreign Application Priority Data May 30, 1969 Switzerland..8228/69 [52] US. Cl. ..260/286 R, 260/283 R, 260/283 S,

260/283 CN, 260/286 Q, 260/287 R, 260/289 R, 260/649 R, 424/258 [51]Int. Cl. ..C07d 39/00 [58] Field of Search ..260/289 R, 286 R, 283 R[56] References Cited UNITED STATES PATENTS 3,518,270 6/1930 Shavel eta1. ..260/286 FOREIGN PATENTS OR APPLICATIONS 1,035,141 1/1959 Germany..260/289 R 1 Feb. 20, 1973 OTHER PUBLICATIONS Primary ExaminerDonald G.Daus AttorneyKar1 F. Jorda and Bruce M. Collins This application filedunder rule 47a.

[ 5 7 ABSTRACT Compounds of the class of 5,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5,l l-imine and the pharmaceuticallyacceptable acid addition salts thereof have anti-tussive andsimultaneously musculotropic spasmolytic activities; they are the activeingredients of pharmaceutical compositions and can be used for thetreatment of tussive irritation; an illustrative embodiment is2-methoxy-5 ,6,1 1,12- tetrahydrodibenzo a,e cycloocten-S ,1 1 -iminehydrochloride.

3 Claims, No Drawings compounds of the formula 1,

DERIVATIVES'OF DIBENZO CYCLOOCTEN-S ,l l-

IMINE DETAILED DESCRIPTION The present invention relates to newderivatives of dibenzo[a,e]cycloocten-5,1l-imine and theirpharmaceutically acceptable acid addition salts having valuablepharmacological properties, to pharmaceutical compositions containingthem and to the use thereof.

More particularly, the present invention relates to l NH k (I) wherein Xand Y independently of each other are hydrogen, alkoxy containing atmost four carbon atoms or together are methylenedioxy,

and the pharmaceutically acceptable acid addition salts thereof.

These compounds have been found to possess valuable pharmacologicalproperties, especially antitussive effectiveness, which are combinedwith a favorable therapeutic index. They lack the analgesic propertiesof codeine-like anti-tussives. At the same time, the compounds offormula] have musculotropic spasmolytic effectiveness, whilst theirneurotropic spasmolytic effect is very slight.

Compounds of formula I and their pharmaceutically acceptable acidaddition salts are used as active ingredients in pharmaceuticalcompositions for oral, rectal or parenteral administration. Thecompounds of formula I and the pharmaceutical compositions containingthem are useful for the relief and cure of tussive irritation inmammals.

In the compounds of formula I and in the starting materials, mentionedbelow, X and Y as lower alkoxy containing at most four carbon atoms, arefor example methoxy, ethoxy, propoxy or butoxy.

Preferred compounds are the compounds of formula I wherein both X and Yare hydrogen, further wherein X is methoxy and Y is hydrogen, and X andY together form the methylenedioxy group, as well as the hydrochloridesthereof.

Compounds of formula I and their acid addition salts are produced byallowing to act on a compound of formula II,

N ll/ Y 2 wherein The hydrogenolysis is carried out, e.g. by means ofhydrogen in the presence of noble metal catalysts such as e.g. platinum,or, in particular, palladium on charcoal or on earth metal carbonates.Also platinum oxide, or alloy-skeleton catalysts such as, e.g. Raneynickel, can be used. Normal pressure and room temperature are usuallysufficient, however, if necessary, especially when Raney nickel is used,pressure and/or temperature are moderately increased. Suitable solventswherein the hydrogenolysis can be carried out are, e.g. ethanol,methanol, dimethylformamide or acetic acid. As acid addition salts,hydrochlorides can be used, which are applied either as such or areformed in situ by the addition of the corresponding amount or of amoderate excess of hydrochloric acid to the prepared solution of thebase.

Starting materials of formula II are embraced by the below given formulaIV and they can be analogously produced by the processes stated forthose compounds.

According to a second process, compounds of formula I and their acidaddition salts are produced by hydrolyzing a compound of formula III,

yll/

Ac (III) wherein Ac is the acyl group of an organic acid, and

X and Y have the meanings given under formula I, and

optionally, converting an obtained compound of formula I into an acidaddition salt or, on the other hand,

liberating the base from an obtained acid addition salt.

In the starting materials of formula III, Ac is, in particular, the acylgroup of cyanic acid, chloroformic acid, of

a carbonic acid or a thiocarbonic acid semi-ester, of a loweralkanecarboxylic acid or of an arenecarboxylic acid. Examples of suchacyl groups are: the cyano, chlorocarbonyl, methoxycarbonyl,ethoxycarbonyl, isobutoxycarbonyl, tert. butoxycarbonyl,phenoxycarbonyl, benzyloxycarbonyl, methoxythiocarbonyl,methylthio-thiocarbonyl, acetyl and benzoyl groups.

The hydrolysis of compounds of formula III is perfonned, for example, byheating such compounds for several hours in an alkanolic oraqueous-alkanolic alkali hydroxide solution, e.g. by boiling in amixture of potassium or sodium hydroxide with ethanol or methanol and alittle water. Instead of lower alkanols, it is also possible to useother solvents containing hydroxyl groups, such as ethylene glycol andits lower monoalkyl ethers. Furthermore, hydrolysis is possible,particularly of compounds of formula III, wherein Ac denotes CN, theacyl radical of the cyanic acid, by heating with wherein R is loweralkyl having at most six carbon atoms, ally] or benzyl, and

X and Y have the meanings given under formula I, by allowing to act onthe stated compounds an organic acyl halide, e.g., a cyanogen halide,especially cyanogen bromide, also phosgene, a chloroformic acid alkylester, the chloroformic acid phenyl ester or benzyl ester, 21 chlorideor bromide of a lower alkanoic acid or of benzoic acid, particularlyacetyl chloride, acetyl bromide or benzoyl chloride, at room temperatureor at elevated temperature, whereby the desired acylation occurs withliberation of the alkyl, allyl or benzyl halide corresponding to thegroup R. The reaction is performed in an inert organic solvent such as,e.g., chloroform or benzene, or optionally also in an excess of anacylhalide which is suitable as reaction medium.

The intermediates of formula IV are produced by allowing to act on adihydroisoquinoline compound of formula V,

wherein R, X and Y have the meanings given respectively under formula IVand formula I, a concentrated mineral acid in the presence or absence ofa lower alkanoic acid as reaction medium.

As mineral acid, phosphoric acid ispreferably used and, as reactionmedium, formic acid or acetic acid are preferably used, at roomtemperature to the boiling temperature of the reaction mixture, if, inthe starting material, at least X denotes a lower alkoxy group. In thecase of starting materials with hydrogen atoms as X and Y, the ringclosure is performed, e.g., by heating for periods ranging from severalto many hours in phosphoric acid to ca. l40-l 70.

The dihydroisoquinoline compounds of formula V are obtainable, e.g.,from l-benzylisoquinoline or from l-benzylisoquinolines, substituted inthe benzyl group corresponding to the definition for X and Y, byquaternizing with a benzyl or allyl halide, with an alkyl halide havingtwo to six carbon atoms or, when the l-benzyl group of the isoquinolineis substituted, also with a methyl halide, and reducing an obtainedisoquinolinium halide by means of a complex hydride, e.g., of lithiurnaluminum hydride in ether, or by catalytic hydrogenation until theabsorption of the equimolar amount of hydrogen is effected, e.g., atroom temperature and under normal pressure in the presence of platinumoxide in methanol or in ethanol which contains an equimolar amount ofsodium methoxide or sodium ethoxide. f the isoquinoline derivativesnecessary for the quaternization, the l-benzylisoquinoline and thel-benzylisoquinoline and the l-veratrylisoquinoline are known. Theothers are produceable analogouslyto the known compounds. For example,the l-(m-methoxybenzyl)-isoquinoline is obtained by condensation of thesodium compound of the known 1- cyano-Z-benzoyl-l,Z-dihydroisoquinoline,produced, e.g., by means of sodium hydride in dimethylformamide, withm-methoxybenzylbromide to give the l-(mmethoxybenzyl)-2 benzoyl-l,Z-dihydroisoquinaldonitrile and hydrolysis of the latter with potassiumhydroxide in boiling ethanol.

According to a further process, intermediates of formula IV, whereinboth X and Y are hydrogen, are produced by reacting the 5,1l-dibromo-5,6,l 1,12- tetrahydrodibenzolaplcyclooctene of formula VI,

sin

B (VI) with a primary amine of formula VII,

R NH

wherein R has the meanings given in formula IV,

in the presence of an acid-binding agent. Used as acidbinding agent ispreferably an, at least, double molar excess of amine of formula VII.This amine can, at the same time, serve as sole reaction medium, but itis also possible to add an inert organic solvent such as, e. g. benzene,toluene or ethanol. The reaction is performed preferably at temperaturesbetween and if necessary, in a closed vessel.

The compounds of formula I are obtained as racemates. If desired, theseracemates can be separated into the optically active isomers in thenormal manner by salt formation with an optically active acid. By thismeans diastereoisomeric salts with different physical properties areobtained.

All the optically active forms of the compounds of formula I also fallwithin the scope of the instant invention.

For use as pharmaceuticals, the compounds of formula I may betransferred into pharmaceutically acceptable acid addition salts, i.e.,salts with inorganic or organic acids, the anions of which are non-toxicand pharmaceutically acceptable if administered in therapeutic doses. Itis also of advantage if such salts to be used in pharmaceuticalcompositions crystallize well and are not, or are only slightlyhygroscopic.

For salt formation with compounds of formula I, it is possible to use,e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid,B-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid,citric acid. lactic acid, succinic acid, fumaric acid, maleic acid,benzoic acid, salicylic acid, phenylacetic acid, .mandelic acid, embonicacid or 1,5- naphthalenedisulphonic acid.

Such salts are formed in a conventional manner. For example, the acid ora solution thereof, which is desired as the salt component, is added toa solution of a compound of formula I in an organic solvent such as,benzene, diethyl ether, methanol, ethanol or acetone, and the salt,which has precipitated immediately or after the addition of a secondorganic liquid such as, e.g., acetone to methanol, is separated. Theliberation of the bases from their acid addition salts is likewisecarried out in the usual manner by reaction with basic substances suchas, e.g., sodium carbonate or sodium hydrogen carbonate.

' und Pharmakol.215, 19-24 (1952). In this test the hydrochlorides ofZ-methoxy-S ,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-S,1 l-imine, of5,6,1 1,] 2-tetrahydrodibenzo[a,e]cycloocten-5,1 1- imine and of2,3-methylenedioxy-5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,ll-imine are shown to be active, for example, upon intravenousadministration in amounts of about 0.5 to about 3 mg/kg.

The musculotropic spasmolytic properties are demonstrated on theisolated intestine of the guinea pig.

The toxicity of the compounds of the invention is of favorable loworder.

For their intended use as anti-tussives, the compounds of the inventionare administered in amounts depending on the species, age, weight andthe particular condition of the subject under treatment and the mode ofadministration. In general the daily dosages vary between about 0.1 andabout 5 mg/kg for warmblooded animals. Suitable dosage units such asdragees, capsules, tablets, suppositories or ampoules, preferablycontain 1-50 mg of a compound of formula I or of a pharmaceuticallyacceptable acid addition salt thereof.

Dosage units for oral administration preferably contain as activesubstance between 1 percent and 90 percent of a compound of formula I,or of a pharmaceutically acceptable acid addition salt thereof. Tabletsor dragee cores are produced by combining the active substance withsolid pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, maize starch or amylopectin,also laminaria powder or citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants, such as magnesiumor calcium stearate or polyethylene glycols, and pressing the mixturesinto the desired form. The latter are coated, e.g., with concentratedsugar solutions which can also contain, e.g., gum arabic, talcum and/ortitanium dioxide, or with a lacquer dissolved in readily volatileorganic solvents or mixtures of solvents. Dyestuffs can be added tothese coatings, e.g., to distinguish between varying dosages of activesubstance. Further suitable oral dosage units are hard gelatine capsulesas well as soft closed capsules made from gelatine and a softener, suchas glycerin. The former preferably contain the active substance as agranulate in admixture with lubricants such as talcum or magnesiumstearate and, optionally, stabilizers such as sodium metabisulphite orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as liquid polyethyleneglycols, whereby stabilizers can likewise be added.

Also suitable for the treatment of the cough are sucking tablets as wellas oral preparations which are not administered in a single dosage suchas cough syrups and cough drops which are prepared with the usualauxiliary agents.

Suitable dosage units for rectal administration are suppositoriesconsisting of a combination of a compound of formula I, or of a suitableacid addition salt thereof, with a neutral fatty base. Also suitable aregelatine rectal capsules containing a combination of the activesubstance with polyethylene glycols.

Ampoules for parenteral, especially intramuscular and intravenousadministration, preferably contain a water-soluble salt of a compound offormula I in a concentration of preferably 0.5-5 percent, optionallytogether with suitable stabilizing agents and butter substances inaqueous solution.

The following examples further illustrate the production of compounds offormula I and of intermediates not described hitherto. The examplesshould not be construed as a limitation of the scope of the presentinvention. The temperatures are given in degrees Centigrade.

EXAMPLE 1 a. Nitrogen gas is fed into the reaction mixture during thewhole reaction period.

150.0 g of 1-cyano-2-benzoyl-l,2-dihydroisoquinoline [produced accordingto the specification of J .J. Padburry and I-I.G. Lindwall, J.Amer.Chem. Soc. 67, 1268 (1945)]are dissolved in 1,500 ml of distilleddimethylformamide and the solution is cooled with an ice bath to 2. Tothe solution are then added in portions over 2 h hrs., whilst stirringproceeds and cooling is applied by means of an ice bath, 30.0 g ofsodium hydride dispersion (50 percent sodium hydride in mineral oil),whereby the temperature is maintained between 0 and 7. 122.0 g of3-methoxybenzyl bromide [produced according to the specification of W.Q.Beard, D.N. van Eenam and Ch.R. Hauser, J.Org. Chem. 26, 2310 (1961)]arethen added dropwise within 2 k hours at between 0 and 5, whilst stirringis continued, to the dark brown solution, whereby a pale precipitate isobtained. The reaction mixture is subsequently stirred for 2 hours atroom temperature and the precipitate then filtered off under suction andwashed with a little dimethylformamide. The filtrate is greatlyconcentrated in a rotary evaporator at -85 and the oil remainingdissolved in 1,500 ml. of ethanol. The solution is allowed to stand,whilst being cooled,

whereupon the 1-(3-methoxybenzyl)-2 benzoyl-1,2

dihydroisoquinaldonitrile, MP. 161 -163, crystallizes out. The yield is135.0 g, 61.7 percent of the theoretical value.

b. 130.0 g of 1-(3-methoxybenzyl)-2-benzoyl-1,2-dihydroisoquinaldonitrile are well mixed with a solution of 108.0 g ofpotassium hydroxide in 325 ml of ethanol and the suspension is refluxedfor one hour, whereby the starting material does not completely go intosolution. To the reaction mixture are added 325 ml of water andrefluxing is then continued for a further 2 hours. The ethanol isafterwards evaporated off at 50in the rotary evaporator, the mixtureremaining diluted with 200 ml of water and repeatedly extracted withether. The ether extracts are combined, washed once with water and driedover sodium sulphate. After the solvent has been evaporated off at 50 inthe rotary evaporator, the 1-(3-methoxybenzyl)-isoquinoline remainsbehind as light-yellow oil. The yield is 83.0 g, 97.5 percent of thetheoretical value.

0. 166.0 g of crude 1-(3-methoxybenzyl)-i1soquinoline are dissolved in590 m1 of nitromethane. To the solution are added 83 ml of benzylbromide and the reaction mixture is refluxed for 3 hours. The solutionis afterwards thoroughly concentrated by evaporation at 60 in a rotaryevaporator, the oil remaining dissolved in 100 ml of methanol and to thesolution are added 1,300 ml of boiling acetone. The solution is allowedto stand, whilst being cooled, whereupon the 1-(3-methoxybenzyl)-2-benzylisoquinolinium bromide, M.P. 177-l78,crystallizes out; the yield is 261.0 g, 93.3 percent of the theoreticalvalue.

d. 125.0 g of pulverized l-(3-methoxybenzy1)-2- benzylisoquinoliniumbromide are introduced in portions, whilst vigorous stirring ismaintained and over a period of 1.5 hours, into a suspension of 60.0 gof lithium aluminum hydride in 2,500 ml of abs. ether, whereby anexothermic reaction occurs. The reaction mixture is subsequently stirredfor 18 hours at room temperature, then cooled with an ice bath to 5 andthe excess lithium aluminum hydride decomposed, whilst the reactionmixture is being stirred and also cooled by means of an ice bath, by thedropwise addition of a mixture of 500 m1 of ethylacetate and 1,000 ml ofbenzene. To the mixture is then added a solution of 800.0 g of potassiumsodium tartrate tetrahydrate (Seignettes salt) in 1,000 ml of water. Themixture is then stirred for 20 minutes at room temperature, the organicphase separated and the aqueous part extracted twice with a mixture ofbenzene/ether (1:1). The organic extracts are combined, washed twicewith water and dried over sodium sulphate in a nitrogen atmosphere.After the solvent has been evaporated off in a rotary evaporator at 50,the oily 1-(3-methoxybenzyl)-2-benzyl-1,2- dihydroisoquinoline isobtained.

e. A mixture of 2,000 ml of anhydrous formic acid and 400 ml of 85percent orthophosphoric acid is added all at once to 182.0 g of crudel-(3-methoxybenzyl)-2-benzyl-1,2-dihydroisoquinoline and the whole wellmixed, whereby a black-violet dyed solution is immediately formed. Thereaction mixture is subsequently refluxed for 24 hours. The red solutionis thereupon cooled to room temperature, poured onto about 2,000 g ofice and, whilst the solution. is being cooled with an ice bath andstirred, the pl-l-value is adjusted to 910 by the addition of 2,000 mlof concentrated aqueous ammonium hydroxide solution and then of 40percent aqueous sodium hydroxide solution. The final volume isapproximately liters. The solution is then repeatedly extracted, in 5portions, with a mixture of benzene/ether (1:1). The combined organicextracts are washed with water, dried over sodium sulphate and thesolvent is evaporated off at 50 in a rotary evaporator. The oilremaining solidifies on being mixed with a little ethanol. Afterrecrystallization from ethanol, the l3-benzyl-2-methoxy-5 ,6,1 1, l2-tetrahydrodibenzo[ a,e ]cycloocten-5,1l-imine melts at 96-99. Theyield is 140.0 g, 76.9 percent of the theoretical value.

f. A solution of 21.0 g of l3-benzyl-2-methoxy- 5 ,6,1l,12-tetrahydrodibenzo[a,e]cycloocten-5 ,l limine in 250 ml of methanolis shaken, under normal pressure and at room temperature under hydrogen,with 2.0 g of 5 percent palladium charcoal and 27.4 ml of ethanolichydrogen chloride solution [containing 16.4 percent (weight/volume) ofhydrogen chloride in 96 percent ethanol]. The hydrogen absorption ceasesafter approximately 27 hours. The catalyst is then filtered off undersuction, washed with 100 ml of then made alkaline with solid sodiumcarbonate and repeatedly extracted with benzene. The benzene extractsare combined, washed with water and dried over sodium sulphate. Afterthe benzene has been evaporated off in a rotary evaporator at 50, the2-methoxy- 5 ,6,1 l ,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 limine isobtained, M.P. -131.

EXAMPLE 2 a. A solution of 23.0 g of sodium in 500 ml of absoluteethanol is heated to 50 and to this solution are then added 122.0 g ofS-hydroxybenzaldehyde and the whole stirred for one hour at 50. 108 mlof lbromobutane are then added dropwise and the reaction mixture isrefluxed for 18 hours. The ethanol is afterwards evaporated off at 50 ina rotary evaporator, the oil remaining taken up in ether and the ethersolution repeatedly washed with water. The ether phase is dried oversodium sulphate, the ether distilled off in the rotary evaporator at 50and the oil remaining fractionated. The 3-butoxybenzaldehyde boils at148-153 /l6 Torr. The yield is 131.0 g, 73.6 percent of the theoreticalvalue.

b. A solution of 130.0 g of 3-butoxybenzaldehyde in 500 ml absoluteether is added dropwise, whilst vigorous stirring is maintained andwithin 2 k hours, to a suspension of 25.0 g of lithium aluminum hydridein 1,000 ml of absolute ether and the reaction mixture stirred for afurther 1 k hours at room temperature. The excess lithium aluminumhydride is subsequently decomposed, whilst the reaction mixture is beingcooled with an ice bath and vigorously stirred, by the dropwide additionof 75 ml of water and 25 ml of 2N sulphuric acid. The suspension is thenstirred for 30 minutes at room temperature, the solid precipitatefiltered off under suction and subsequently washed with benzene. Thefiltrate is dried over sodium sulphate, the solvent distilled off at 50in the rotary evaporator and the oil remaining fractionated. The3-butoxybenzylalcohol boils at 165-168l16 Torr. The yield is 117.0 g, 89percent of the theoretical value.

c. A solution of 50.0 g of 3-butoxybenzyl alcohol in 300 ml of abs.ether is added dropwise, whilst stirring is maintained and coolingapplied by means of an ice bath, to a solution of 50.0 g of phosphorustribromide in 500 ml of absolute ether. The reaction mixture issubsequently stirred for 18 hours at room temperature. It is thereuponcooled with an ice bath, 150 ml of ice cold water are added and thewhole is stirred for 30 minutes. The organic phase is then separated,washed twice with 50 ml of saturated sodium hydrogen carbonate solutioneach time, dried over sodium sulphate, the solvent distilled off in arotary evaporator at 50 and the oil remaining fractionated. The3-butoxybenzyl bromide boils at 159-161/l5 Torr. The yield is 59.7 g,88.7 percent of the theoretical value.

d. Nitrogen is fed into the reaction mixture throughout the reactionperiod.

62.0 g of l-cyano-Z-benzoyl-l ,Z-dihydroisoquinoline [cp. Example 1 (a)]are dissolved in 600 ml of dimethylformamide and the solution is cooledwith an ice bath to 2. To the solution are then added in portions over 1/2 hours, whilst the solution is being cooled with an ice bath andstirred, 12.0 g of sodium hydride dispersion (50 percent sodium hydridein mineral oil), whereby the temperature is maintained between and 7.59.5 g of 3-butoxybenzyl bromide are then added dropwise at between 0and 5, within 2 )6 hours and whilst stirring is maintained, to the darkbrown solution, whereby a pale precipitate is obtained. The reactionmixture is subsequently stirred at room temperature for 2 b hours, theprecipitate then filtered off with suction and washed with a littledimethylformamide. The filtrate is thoroughly concentrated byevaporation at 8085 in a rotary evaporator, the oil remaining taken upin chloroform and the solution repeatedly washed with water. After thesolvent has been evaporated off in a rotary evaporator at 50, the oilyl- (3 -butoxybenzyl )-2 -benzoyl- 1 ,Z-dihydroisoquinaltained from 81.0g of crude l-(3-butoxybenzyl)-2- benzoyl-l ,2-dihydroisoquinaldonitrileby boiling with a solution of 67.0 g of potassium hydroxide in 200 ml ofethanol or 200 ml of water, analogously to Example 1 (b). The yield is50.0 g, 89.7 percent of the theoretical value.

f. 50.0 g of oily l-(3-butoxybenzyl)-isoquinoline are dissolved in 200ml of nitromethane. To the solution are then added 23 ml of benzylbromide and the whole is refluxed for 3 hours. The nitromethane isthereupon evaporated off at 50 in a rotary evaporator and the oilremaining mixed with 400 ml of hot acetone. The mixture is allowed tostand, whilst being cooled, whereupon thel-(3-butoxybenzyl)-2-benzylisoquinolinium bromide, M.P. l62-l64-",crystallizes out. The yield is 38.5 g, 48.4 percent of the theoreticalvalue.

g. The oily l-(3-butoxybenzyl)-2-benzyl-1,2- dihydroisoquinoline isformed by the reduction of 42.0 g ofl-(3-butoxybenzyl)-2-benzylisoquinolinium bromide with 20.0 g of lithiumaluminum hydride in 800 ml of absolute ether, analogously to Example 1(d). 'The yield is 34.0 g, 97.8 percent of the theoretical value.

h. A mixture of 400 ml of anhydrous formic acid and 80 ml of 85 percentorthophosphoric acid is added all at once to 34.0 g of crudel-(3-butoxybenzyl)-2- benzyl-1,Z-dihydroisoquinoline. The whole is wellmixed and the black-violet solution refluxed for 20 hours. The reactionmixture is subsequently cooled to room temperature. Approximately 250 mlof formic acid are evaporated off in the rotary evaporator at 60. Thesolution which remains is then poured on to ice and, whilst the solutionis being cooled with an ice'bath and stirred, the pl-l-value is adjustedto 9-10 by the addition of 150 ml of concentrated aqueous ammoniumhydroxide solution and then of 40 percent aqueous sodium hydroxidesolution. The solution is afterwards repeatedly extracted with a mixtureof benzene/ether (1:1). The organic extracts are combined washed withwater, dried over sodium sulphate and the solvent is distilled off inthe rotary evaporator at 50. The oil which remains (33.0 g) is thenchromatographed on 1,250 g of silica gel with a mixture ofbenzene/chloroform/ethanol (51510.1) as the solvent. Thel3-benzyl-2-butoxy-5,6,l 1,12- tetrahydrodibenzola,e]cycloocten-S,1 limine, obtained by evaporation of the eluate, is oily. The yield is 17.3g, 50.9 percent of the theoretical value.

i. A solution of 1.0 g of oily 13-benzyl-2-butoxy- 5 ,6,11,12-tetrahydrodibenzo[a,elcycloocten-S ,1 1- imine in 40 ml of methanolis shaken with 0.20 g of 5 percent palladium charcoal and 0.85 ml ofethanolic hydrogen chloride solution [containing 16.4 percent(weight/volume) of hydrogen chloride in 96 percent ethanol] under normalpressure and at room temperature under hydrogen. The hydrogen absorptionceases after about 23 hours. The catalyst is thereupon filtered offunder suction, washed with a little methanol and the filtrateconcentrated by evaporation to dryness in the rotary evaporator at 50.The solid product which remains is recrystallized from a mixture ofbenzene/ethanol (a little)/petroleum ether. The 2-butoxy-5 ,6,ll,1Z-tetrahydrodibenzo[a,e]cycloocten- 5,11-imine hydrochloride melts at160-164 with decomposition, The yield is 0.68 g, percent of thetheoretical value.

' EXAMPLE 3 a. A mixture of 15.2 g of 5,ll-dibromo-5,6,1l,l2-tetrahydrodibenzola,e]cyclooctene [produced according to thespecification of A.C. Cope and S.W. Fenton, J.Am.Chem.Soc. 73, 1668(1951)] and 120 ml of benzylamine is heated for 18 hours to 140. Theexcess benzylamine is then evaporated off at in the rotary evaporator,the residue mixed with 5 percent aqueous ammonium hydroxide solution andrepeatedly extracted with ether. The ether extracts are combined, washedwith water, dried over sodium sulphate and the ether is distilled off.The oil which remains behind is subsequently heated for 2 hours to l40/0.1 Torr, then cooled to room temperature, dissolved in ether andfiltered through g of aluminum oxide (Woelm, activation stage III) withether as the solvent. After the ether has been evaporated off at 50 inthe rotary evaporator, the oily l3-benzyl-5 ,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 l-imine remains behind. it isdissolved in a little acetone, to the solution is added a slight excessof ethereal hydrogen chloride and the solution allowed to stand, wherebythe solid hydrochloride precipitates. The 13-benzy1-5,6,1 1,12-tetrahydrodibenzo a,e cycloocten-S ,1 l-imine hydrochloride melts at194-198 with decomposition. Yield 13.55 g, 94 percent of the theoreticalvalue.

b. A solution of 12.0 g 'of l3-benzyl-5,6,l1,12- tetrahydrodibenzo[a,eIcycloocten-S ,1 l-imine hydrochloride in 250 ml of absolute ethanol isshaken with 3.0 gof 10 percent palladium charcoal under normal pressureand at room temperature under hydrogen. The hydrogen absorption ceasesafter approximately 4 hours. The catalyst is thereupon filtered off, thefiltrate evaporated off at 50 in the rotary evaporator and the solidresidue crystallized from a mixture of methanol and acetone. The 5,6,11,12- tetrahydrodibenzo a,e ]cycloocten-S l l-imine 'hydrochloridesublimes at 290295. Yield 8.0 g, 90

percent of the theoretical value. The free base is obtained by addingconcentrated sodium carbonate solution to the aqueous suspension of thehydrochloride and extraction with ether. The ether extract is washedwith water, dried over sodium sulphate and the solvent evaporated off at50 in the rotary evaporator. After recrystallization from a mixture ofethanol and water, the 5,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-5,llimine melts at 9698.

EXAMPLE 4 A suspension of 8 g 13-benzyl-2-methoxy-5,6,l1,12-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine and 2.0 g Raney nickel in100 ml absolute ethanol are stirred in a hydrogen atmosphere at 80 barand 80. After absorption of approximately 60 percent of the calculatedamount of hydrogen a further 2.0 g of Raney nickel are added and thehydrogenation is continued under the above conditions.

After about 1 1 hours the absorption of hydrogen has practically ceased.The catalyst is then removed by filtration under suction, washed with100 ml ethanol and the filtrate evaporated to dryness in a rotaryevaporator at 50.

The residual oil is dissolved in 250 ml of a mixture benzene-ether(1:1), the solution washed successively with 2 n sodium carbonatesolution and water, dried over sodium sulphate and the solvent isevaporated off in a rotary evaporator at 50. Finally the oily product(6.0 g) is chromatographed on 200 g of silica gel with a mixture ofbenzene-ethanol (:05) as solvent. After recrystallization from methylenechloride/ether the 2- methoxy-5,6,l1,12-tetrahydro-dibenzo[a,e]cyc1oocten-5,1l-imine melts at ll6l19. Yield1.88 g, 31,9 percent of theoretical volue.

EXAMPLE 5 a. 30.0 g of l-cyano-Z-benzoyl-l,Z-dihydroisoquinoline[produced as in Example 1 (a)] are benzylated by successive reactionwith 6.0 g of sodium hydride dispersion (50 percent sodium hydride inmineral oil) and 27.0 g of 4-(bromoethyl)-veratrole [veratryl bromide,produced according to the specification of R.D.

Haworth, W.l-l. Perkin and J. Rankin, Soc. 127, 1444 1925)]in 375 ml ofdimethylformamide, analogously to example 2(d). The obtainedl-veratryl-2-benzoyl- 1,2-dihydroisoquinaldonitrile is oily. The yieldis 47.0 g, 99.4 percent of the theoretical value.

b. The oily l-veratrylisoquinoline is produced by the boiling of 47.0 gof crude l-veratryl-2-benzoyl-l,2- dihydroisoquinaldonitrile with asolution of 35.0 g of potassium hydroxide in 200 ml of ethanol or in 200ml of water, analogously to Example 1( b). The yield is 20.0 g, 91.4percent of the theoretical value.

c. The 1-veratryl-2-benzylisoquinolinium bromide,

M.P. 180-184 (after recrystallization from a mixture of chloroform andacetone) is obtained by the reaction of 35.0 g of crudel-veratrylisoquinoline with 18 ml of benzyl bromide in 120 ml ofnitromethane, analogously to Example 2(f). The

yield is 12.0 g, 21.2 percent of the theoretical value.

d. The oily l-veratryl-2-benzyl-l,Z-dihydroisoquinoline is produced bythe reduction of 12.0 g of 1- veratryl-Z-benzylisoquinolinium bromidewith 6.0 g of lithium aluminum hydride in 250 ml of absolute ether,analogously to Example 1(d). The yield is 9.7 g, 98.4 percent of thetheoretical value.

c. 10.3 g of lveratryl-2-benzyl-l,2-dihydroisoquinoline are cyclized byboiling with a mixture of 125 m1 of anhydrous formic acid and 25 ml ofpercent orthophosphoric acid, analogously to Example 2(h). Afterrecrystallization from ethanol, the l3-benzyl-2,3- dimethoxy-S ,6,1 1, l2-tetrahydro-dibenz0[ a,e] cycloocten-5,1l-imine melts at ll9l23. Theyield is 2.8 g, 27.2 percent of the theoretical value.

f. A solution of 5.30 g of l3-benzyl-2,3-dimethoxy- 5 ,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 1- imine in ml of methanol isshaken with 1.0 g of 5 percent palladium charcoal and 3.60 ml ofethanolic hydrogen chloride solution [containing 14.3 percent(weight/volume) of hydrogen chloride in ethanol]ethanol] under normalpressure and at room temperature in a hydrogen atmosphere. The hydrogenabsorption ceases after about 4 9% hours. The catalyst is then filteredoff under suction, washed with 50 m1 of methanol and the filtrateconcentrated by evaporation to dryness in the rotary evaporator at 50.The solid residue is subsequently recrystallized from methanol. The2,3-dimethoxy-5 ,6, l l, l 2-tetrahydrodibenzo[ a,e,]cycloocten-5,ll-imine hydrochloride melts at 279282 with decomposition. (in a smallsealed tube). Yield 3.0 g, 66.2 percent of theoretical value.

EXAMPLE 6 a. 80.0 g of l-cyano-2-benzoyl-l,2-dihydroisoquinoline[produced as in example 1 (a)] are benzylated by successive reactionwith 16.0 g of sodium hydride dispersion (50 percent sodium hydride inmineral oil) and 70.0 g of 1 (bromomethyl)-3,4-methy1enedioxybenzene[piperonyl bromide, produced according to the specification of P.Karrer, H. l-lorlacher, F. Locher and M. Giesler, l-lelv. 6, 905 (1923)]in 850 m1 of dimethylformamide, analogously to Example 2(d). Theobtained l-piperonyl-2-benzoyl-1 ,2-dihydroisoquinaldonitrile is oily.The yield is l 10 g, 90.7 percent of the theoretical value.

b. The oily l-piperonylisoquinoline is produced by the boiling of 143.0g of crude 1-piperony1-2-benzoy1- 1,2-dihydroisoquinaldonitrile with asolution of 120.0 g of potassium hydroxide in 350 ml of ethanol or in350 ml of water, analogously to Example 1(b). The yield is 70.0 g, 73.3percent of the theoretical value.

c. The l-piperonyl-2-benzylisoquinolinium bromide, M.P. 209-2l4 (afterrecrystallization from a mixture of methanol and acetone) is obtained bythe reaction of 70.0 g of crude l-piperonylisoquinolinewith 30 ml ofbenzyl bromide in 250 m1 of nitromethane, analogously to Example 2 (f).The yield is 50.0 g, 43.4 percent of the theoretical value.

d. The oily lpiperonyl-2-benzyl-l ,Z-dihydroisoquinoline is produced bythe reduction of 20.0 g of lpiperonyl-2-benzylisoquinolinium bromidewith 10.0 g of lithium aluminum hydride in 500 m1 of absolute ether,analogously to example 1(d). The yield is 16.0 g, 97.7 percent of thetheoretical value.

e. 16.0 g of l-piperonyl-2-benzyll ,2- dihydroisoquinoline are cyclizedby boiling with a mixture of 175 ml of anhydrous formic acid and 35 mlof 85 percent orthophosphoric acid, analogously to example 2 (h). Theoily crude product l 1.0 g) is chromatographed on 500 g of silica gelwith a mixture of benzene/chloroform/ethylacetate (52520.5) as solvent.After recrystallization from ethanol, the l3-benzyl-2,3-methylenedioxy-S ,6,1 l ,12-tetrahydrodibenzo[a,e ]cycloocten-5,ll-imine melts at 135l37. The yield is 6.0 g, 37.5 percent of thetheoretical value.

f. A solution of 5.70 g of l3-benzyl-2,3- methylenedioxy-S ,6,11,12-tetrahydrodibenzo[a,e ]cycloocten-5,l l-imine in 100 ml of methanolis shaken, under normal pressure and at room temperature in a hydrogenatmosphere, with 1.0 g of 5 percent palladium charcoal and 4.1 ml ofethanolic hydrogen chloride solution [containing 14.3 percent(weight/volume) of hydrogen chloride in abs. ethanol]. The hydrogenabsorption ceases after about hours. The catalyst is then filtered offunder suction, washed with 100 ml of methanol and the filtrateconcentrated by evaporation to dryness in the rotary evaporator at 50.The solid residue is subsequently recrystallized from a mixture ofmethanol and acetone. The 2,3- methylenedioxy-S ,6,1 l ,12-tetrahydrodibenzo[ a,e]cycloocten-5,l l-imine hydrochloride melts at247-250 with decomposition (in a small sealed tube). The yield is 3.1 g,64.1 percent of the theoretical value.

EXAMPLE 7 a. A solution of 4.09 g of 13-benzyl-2-methoxy- 5,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 1- imine [cp. examples 1(a) to(e)] and 1.60 g of cyanogen bromide in 15 ml of chloroform is refluxedfor 6 hours. The reaction mixture is then concentrated by evaporation at50 in the rotary evaporator and the oil which remains behindchromatographed on 450 g of silica gel with a mixture ofbenzene/chloroform (1:1) as solvent. The 2-methoxy-5 ,6,1 l, l2-tetrahydrodibenzo[ a,e]cycloocten-5,l l-imine-l3-carbonitrile boils at2l0220/0.00l Torr. Yield 2.64 g, 79.7 percent of the theoretical value.

b. A mixture of 2.0 g of 2-methoxy-5,6,l 1,12-tetrahydrodibenzo[a,e]cycloocten-5,l l-imine-l 3-carbonitrile, ml ofanhydrous formic acid and 4 ml of 85 percent orthophosphoric acid arerefluxed for 20 hours. About 15 ml of formic acid are then distilled offat 60 in the rotary evaporator and the syrup remaining is then pouredonto ice. The solution is thereupon adjusted to pH 9-l0 withconcentrated aqueous ammonium hydroxide solution and repeatedlyextracted with a mixture of benzene/ether (1:1). The organic extractsare combined, washed with water, dried over sodium sulphate and thesolvent is evaporated off at 50 in the rotary evaporator. The oil whichremains behind (1.87 g) is converted, analogously to Example 3(a), intothe hydrochloride. After recrystallization from a mixture of methanoland acetone, the 2-methoxy-5,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5 ,1 l-imine hydrochloride melts at284290 with decomposition. Yield 0.91 g, 47.4 percent of the theoreticalvalue.

EXAMPLE 8 a. A solution of 2.7 g of l3-benzyl-2-methoxy- 5 ,6,1 l,12-tetrahydrodibenzo[a,e]cycloocten-S ,l limine [produced according toExample 1(a) to (e)] in 5.0 ml of chloroformic acid ethyl ester isrefluxed. Since the volume of the reaction mixture decreases, 5.0 ml ofchloroformic acid ethyl ester are added to the latter after 1 A hours.After a total time of 5 hours refluxing, the dark solution is allowed tostand for 18 hours at room temperature, then poured on to water andrepeatedly extracted with benzene. The benzene extracts are combined,successively washed with 1N sodium carbonate solution and with water anddried over sodium sulphate. The benzene is distilled of at 50 in therotary evaporator and the oil which remains (2.7 g) is chromatographedon 350 g of silica gel with a mixture of benzene/ethanol (1010.2) assolvent. The 2- methoxy-5,6,l 1 ,1 2-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine-l3-carboxylic acid ethyl ester boils at 20l (bathtemperature)/0.005 Torr. Yield 1.57 g, 61.3 percent of the theoreticalvalue.

b. 1.07 g of 2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,11-imine-l3-carboxylic acid ethyl ester are well mixed with a solution of10 g of potassium hydroxide in a mixture of 50 ml of ethanol and 2 ml ofwater and subsequently refluxed for 24 hours. The yellow solution isthen poured on to water and repeatedly extracted with benzene. Thebenzene extracts are combined, washed with water and dried over sodiumsulphate. After the benzene has been evaporated off in the rotaryevaporator at 50, the crude 2-methoxy-5,6,l l, l 2-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine remains behind (0.92 g). It is dissolved in 5ml of methanol, the solution made acidic with ethanolic hydrogenchloride and 10 m1 of acetone are then added to the solution. Thesolution is left to stand at room temperature to allow the 2- methoxy-S,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten- 5,1l-imine hydrochloride tocyrstallize out, M.P. 285293, with decomposition. The yield is 0.45 g,47.3 percent of the theoretical value.

EXAMPLE 9 a. 1.0 g l3-methyl-2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5,1l-imine is dissolved in 10 ml acetone, 6 ml of 30percent hydrogen peroxide are added and the solution is allowed to standin a closed flask for 48 hours at room temperature. The solution is thenevaporated to dryness under a water jet vacuum at room temperature(about 24 hours) and finally the residual oil is dried at roomtemperature and 0.05 Torr for 8 hours. The l3-methyl-2-methoxy- 5 ,6,1l, l 2-tetrahydro-dibenzo[a,e ]cycloocten-5 ,l limin-l3-oxide remains asa glassy mass. Yield 1.0 g, 94.3 percent of theoretical value.

b. 0.90 g of l3-methyl-2-methoxy-5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,l l-imin-l 3-oxide is dissolved in 15 ml of aceticanhydride and the reaction mixture boiled for 18 hours under reflux. Theresulting dark brown solution is then poured into water and repeatedlyextracted with benzene. The benzene extracts are combined, washedsuccessively with 2N sodium hydroxide solution, water, 2N hydrochlorideacid and water and dried over sodium sulphate. After evaporation of thesolvent in a rotary evaporator at 50 the resulting oil (0.680 g) ischromatographed on 100 g of Kieselgel with a mixture of benzene-ethanol-(10:0,25) as solvent. The 13-acetyl-2-methoxy- 5,6,1 1,12-tetrahydrodibenzo[a,e]cyc1oocten-5,1 1- imine thus obtained existsas a foam. Yield 0,400 g, 42,6 percent of theoretical value.

c. 0.400 g of 13-acetyl-2-methoxy-5,6,11,12-tetrahydrodibenzo[a,e]-cycloocten-5,1 l-imine are well mixed with asolution of g of potassium hydroxide in a mixture of 25 ml of ethanoland 1 ml of water and then boiled for 24 hours under reflux. The yellowsolution is then poured into water and repeatedly extracted withbenzene. The benzene extracts are combined, washed with water and driedover sodium sulphate. After evaporation of the benzene in a rotaryevaporator at 50, the crude 2-methoxy-5,6,l1,12-tetrahydrodibenzo [a,e]cycloocten-5,11-imine remains (0.31 g). This crude product is dissolvedin 2.5 ml of methanol, the solution acidified with an ethanolic solutionof hydrogen chloride and then mixed with 5 ml of acetone. After beingleft to stand at room temperature, the 2-rnethoxy-5,6,1 l,12-tetrahydrodibenzo[ a,e]cycloocten-S,ll-imine hydrochloridecrystallizes out, M.P. 285-289 (decomposition). Yield 0.17 g, 43 .4percent of theoretical value.

EXAMPLE a. A mixture of 2.0 g 13-benzyl-2,3-methylenedioxy- 5 ,6,11,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 imine, 30 ml of benzene and10 ml of chloroformic acid ethyl ester is boiled for 12 hours underreflux. A further 10 ml of chloroformic acid ethyl ester are then addedand the reaction mixture is again boiled under reflux for 12 hours.Finally a further 5 ml of chloroformic acid ethyl ester are added andthe mixture is boiled under reflux for 6 hours. The resulting darkreaction mixture is diluted with benzene, the benzene solution washedsuccessively with water, 2N hydrochloric acid, water, 2N sodiumcarbonate and water, dried over sodium sulphate and the solventevaporated off in a rotary evaporator at 50. The residual oil solidifieson mixing with a little ether. After recrystallization from a mixture ofmethylene chloride-ether, the 2,3- methyIenediOxy-S ,6,11,12-tetrahydrodibenzol a,e]cycloocten-5,11-imine-13-carboxylic acidethyl ester melts at 133135. Yield 1.170 g, 61.6 percent of theoreticalvalue.

b. Analogously to Example 8(b) 1.170 g of 2.3- methylene-dioxy-S ,6,1 1,12-tetrahydrodibenzol a,e]cycloocten-S,1l-imine-l3-carboxylic acidethyl ester are boiled under reflux with a solution of 10 g of potassiumhydroxide in a mixture of 50 ml of ethanol and 2 ml of water for 24hours, poured into water and repeatedly extracted with benzene. Thebenzene extracts are combined and washed with water. After drying oversodium sulphate the benzene is evaporated in a rotary evaporator at 50and the crude 2,3- methylenedioxy-S ,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine (0.75 g) remains as residue. The correspondinghydrochloride melts at 247-250 with decomposition (in a sealed capillarytube). Yield 0.584 g, 56 percent of theoretical value.

EXAMPLE ll a. 2.0 g of 13-benzyl-2-methoxy-5,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5,l l-imine are dissolved in 20 ml ofbenzene. The solution is mixed with 5 ml of chloroformic acid isobutylester and boiled for 5 hours under reflux. A further 5 ml ofchloroformic.

acid isobutylester are then added to the solution and the reactionmixture is boiled for 18 hours under reflux. The resulting brownsolution is diluted with benzene washed successively with 2Nhydrochloric acid and water, dried over sodium sulphate and the solventevaporated off in a rotary evaporator at 50. Finally the residual oil ispurified by chromatography on 200 g of silica gel with a mixture ofbenzene-ether (10:05) as solvent. The2-methoxy-5,6,1l,12'tetrahydrodibenzo[ a,e]cyc1oocten 5,1l-imine-13-carboxylic acid isobutyl ester boils at 198-203 (bathtemperature) [0.02 Torr. Yield 2.025 g, 98.3 percent of theoreticalvalue.

b. 1.15 of the isobutyl ester prepared in (a) are hydrolyzed analgouslyto example 8(b) with potassium hydroxide and the 2-methoxy-5 ,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine thus obtained is convertedinto its hydrochloride with an ethanolic solution of hydrogen chloride.M.P. 285-29 3 (with decomposition) Yield 0.463 g, 49.1 percent oftheoretical value.

EXAMPLE 12 Separation of racemic 2-methoxy-5,6,1 1,12- tetrahydro[a,e]cycloocten-5 ,1 l-imine:

A solution of 10.0 g of racemic 2-methoxy- 5,6,11,lZtetrahydrodibenzo[a,e]cycloocteri-5,1 1- imine in 50 ml ofchloroform is mixed with a solution of 15 g of (-)-dibenzoyl tartaricacid monohydrate [{a 81.8 (G -0.967 percent in chloroform)] [preparedaccording to CL. Butler and L.H. Cretcher, J.Amer. Chem. Soc. 55, 2605(1933) in m1 of methanol. The resulting clear solution is allowed tostand for 10 minutes at room temperature and then evaporated to drynessin a rotary evaporator at 50. After three times recrystallizing thesolid residue from a mixture of methanol/ether (1:1), 4.40 g of (+)-2-methoxy-S ,6,1 1 ,1 2-tetrahydrodibenzo[ a,e Icycloocten-5,11-imine-(--)-dibenzoyl-tartrate are obtained. M.P. 193l94.

The above salt (4.40 g) is suspended in water, the suspension is madealkaline to litmus with 2N sodium carbonate solution and repeatedlyextracted with a mixture of benzene/ether (1:1). The organic extractsare combined, washed with water, dried over sodium sulphate and thesolvent evaporated off in a rotary evaporator at 50. After twicerecrystallizing the residual product from a little ether, the(+)-2-methoxy- 5 ,6,1 1 ,1 Z-tetrahydrodibenzo[a,e]cyc1oocten-5 ,1 1-imine obtained melts at 11l112, [a1 +1395 i 4 (c= 0.1 percent inchloroform). Yield 0.670 g, 13.4 percent of theoretical value.

0.55 g of i-)-2-methoxy-5,6,l1,l2-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine are dissolved in 20 ml ofchloroform., the solution is made acid to litmus by the additiondropwise of a methanolic solution of hydrogen chloride (approximately 2Nallowed to stand for 10 minutes at room temperature and finallyevaporated to dryness in a rotary evaporator at 50. After a singlerecrystallization of the residual product from a mixture ofmethanol/acetone (1:1,5), the(+)-2-methoxy-5,6,11,12-tetrahydrodibenzo[a,e ]cycloocten-5,1l-imine-hydrochloride melts at 280-285, [01], 122 i 4 (c=0,l% inmethanol). Yield 0.550 g, 87.5 percent of theoretical value.

The first mother liquor from the solution of the 2-methoxy-5 ,6,11,12-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine-()-dibenzoyl-tartrateis evaporated to dryness in a rotary evaporator at 50. The residual oilis then mixed with water, the aqueous solution made alkaline to litmuswith 2N sodium carbonate solution and repeatedly extracted with amixture of benzene/ether (1:1). The organic extracts are combined,washed with water, dried over sodium sulphate and the solvent evaporatedoff in a rotary evaporator at 50. The residual solid product (4.80 g) isdisolved in 40 ml of chloroform and then mixed with a solution of 4.50 gof (+)-camphorl O-sulphonic acid-(B)-monohydrate[[ a] =+20 1 1 (c=percent in water)] in 70 ml of methanol. The solution in then allowed tostand for 10 minutes at room temperature and finally evaporated todryness in a rotary evaporator at 50. After three times recrystallizingthe residual product from a mixture of methylene chloride/petroleumether (1:4), 3.20 g of (-)-2-methoxy-5 ,6,l 1,12-tetrahydrodibenzo[a,e]cycloocten-S, l 1-imine-(+)-camphor-l0-sulphate, M.P. 220-224, isobtained.

The above salt (3.20 g) is suspended in water, the suspension is madealkaline to litmus with 2N sodium carbonate solution and repeatedlyextracted with a mixture of benzene ether (1:1). The organic extractsare combined, washed with water, dried over sodium sulphate and thesolvent evaporated in a rotary evaporator at 50. After twicerecrystallizing the residual product from a mixture of methylenechloride petroleum ether (1:8), the ()-2-methoxy-5,6,l 1,12-

tetahydrodibenzo[a,ef9 cycloocten-5,l l-imine obtained melts at 102-105[01],, l 11 i 3 (c=0.1 percent in chloroform). Yield 0,980 g, 19.6percent of theoretical value.

0.480g ()-2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5,1l-imine are dissolved in 10 ml of methanol and thesolution made acid to litmus by the addition dropwise of a methanolicsolution of hydrogen chloride (approximately 2N). The solution isallowed to stand for 10 minutes at room temperature and then evaporatedto dryness in a rotary evaporator at 50". After a singlerecrystallization of the residual product from a mixture ofmethanol/ether (123,5), the ()-2-methoxy-5,6,11,12-tetrahydrodibenzo[a,e]cycloocten-5,l l-imine hydrochloride thus obtainedmelts at 272278 [a],, 99.5 :L- 3.5 (c=0,l percent methanol Yield:0.430g,78.3 percent of theoretical value.

The following prescriptions further illustrate the production ofpharmaceutical compositions according to the invention:

EXAMPLE 13 10 g of active substance, e.g., 2-methoxy-5,6,l 1,12-tetrahydrodibenzo[a,e]cycloocten-5 ,1 l-imine hydrochloride, 30 g oflactose and 5 g of highly dispersed silicic acid are mixed together. Themixture is moistened with a solution of 5 g of gelatine and 7.5 g ofglycerin in distilled water, and is then granulated through a sieve. Thegranulate is dried, sieved and carefully mixed with 3.5 g of potatostarch, 3.5 g of talcum and 0.5 g of magnesium stearate. The mixture ispressed into 1.000 tablets each weighing 65 mg and each containing 10 mgof active substance.

EXAMPLE 14 10 g of active substance, e.g., 2-methoxy-5,6,l1,12-tetrahydrodibenzo[a,e ]cycloocten-S ,1 1 -im ine hydrochloride, 15 g oflactose and 20 g of starch are mixed together. The mixture is moistenedwith a solution of 5 g of gelatine and 7.5 g of glycerin in distilledwater and granulated through a sieve. The granulate is dried, sieved andcarefully mixed together with 3.5 g of talcum and 0.5 g of magnesiumstearate. The mixture is then pressed into 1.000 dragee cores. These aresubsequently coated with a concentrated syrup made from 26.66 g ofcrystallized saccharose, 17.5 g of talcum, 1 g of shellac, 3.75 g of gumarabic, l g of highly dispersed silicic acid and 0.090 g of dyestuff,and dried. The obtained dragees each weigh 115 mg and each contain 10 mgof active substance.

EXAMPLE 15 To produce 1.000 capsules each containing 10 mg or 25 mg ofactive substance, 10 g or 25 g of 2-methoxy- 5 ,6,1 l, 12-tetrahydrodibenzo[a,e]cycloocten-S,1 1-

'imine hydrochloride are mixed with 263 g or 248 g of EXAMPLE 16 Toproduce a cough syrup having an active substance content of 0.2 percent,1.5 liters of glycerin, 42 g of phydroxybenzoic acid methyl ester, 18 gof p-hydroxybenzoic acid n-propyl ester and, with slight heating, 20 gof 2-methoxy-5,6,l1,l2-tetrahydrodibenzo[a,e]- cycloocten-5,11-iminehydrochloride are dissolved in 3 liters of distilled water. To this areadded 4 liters of percent sorbitol solution, '1 .000 g of crystallizedsaccharose, 350 g of glucose and an aromatic, e.g., 250 g of Orange PeelSoluble Fluid of ELI LILLY & Co., Indianapolis, or 5 g of natural lemonaroma and 5 g of l-lalb und Halb essence, both of the firm HAAR- MANN &REIMER, Holzminden/Germany. The obtained solution is filtered and thefiltrate is made up with distilled water to 10 liters.

EXAMPLE 17 A cough syrup containing 0.1 percent of active substance isproduced as follows: 10 g of 2,3- methylenedioxy-5 ,6,1 l,12-tetrahydrodibenzo[ a,e]cycloocten-5,ll-imine hydrochloride aredissolved, whilst heat is applied, in a mixture of 2.5 liters and 18 gof p-hydroxybenzoic acid n-propyl ester. This syrup is then carefullymixed with the active substance solution. After addition of aromatics,e.g., those mentioned under (b), and, if necessary, filtration, theobtained syrup is made up with distilled water to l liters.

EXAMPLE 18 To prepare cough drops containing 1.0 percent of activesubstance, 100 g of 2-methoxy-5,6,l 1,12-tctrahydrodibenzo[a,e]cycloocten-5,l l-imine hydrochloride and 3 g ofsaccharine sodium salt are dissolved in a mixture of 4 liters of 70percent of ethanol (96 percent) and 1 liter of propylene glycol. Amixture is prepared separately of 3.5 liters of 70 percent sorbitolsolution with l liter of water and this mixture is then added to theabove active substance solution. An aromatic, e.g., 5 g ofHustenbonbon-Aroma (cough drop aroma) or 30 g of Grapefruit essence,both of the firm HAARMANN & REIMER, Holzminden/Germany, is added, thewhole well mixed, filtered and madeup with distilled water to liters.

EXAMPLE 19 A suppository mixture is prepared from 2.5 g of 5,6,11,l2-tetrahydrodibenzo{a,e]cycloocten-S ,1 limine hydrochloride and167.5 g of adeps solidus and from the mixture are poured 100suppositories each containing 25 mg of active substance.

EXAMPLE 20 X and Y, independently of each other, are hydrogen or allcoxyhaving at most 4 carbon atoms;

and a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim I, which is 2- methoxy-S ,6,1 l,12-tetrahydrodibenzo[a,e]cycloocten- 5,1 l-imine and the hydrochloridethereof.

3. A compound according to claim I, which is 5,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5,1 l-imine and the hydrochloridethereof.

1. A compound of the formula
 2. A compound according to claim I, whichis 2-methoxy-5,6,11, 12-tetrahydrodibenzo(a,e)cycloocten-5,11-imine andthe hydrochloride thereof.